Therapeutic PSA-targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety, prolongation of progression free of survival (PFS), and overall survival, in a randomized, controlled, and blinded phase II study. 125 patients were randomized in a multi-center trial of vaccination series. Eligible patients had minimally symptomatic castration resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises 2 recombinant viral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF + GM-CSF, versus Control empty vectors + saline injections. 2 patients received PROSTVAC-VF and 40 received Control vectors. Patient characteristics were similar. The primary endpoint was PFS, which was similar in the two groups (P=0.6). However, at 3 years post study, PROSTVAC-VF patients had a better overall survival with 25/82 (30%) alive, versus 7/40 (17%) Controls. There was a longer median survival by 8.5 months (24.5 months for vaccine versus 16 months Controls); and estimated hazard ratio 0.56 (95% CI 0.37-0.85); stratified log rank P=0.0061. PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5 month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit, but need to be confirmed in a larger Phase III study, which is currently ongoing. A concurrent randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of immune responses with improved overall survival in patients with the best immune response. This study employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. 32 patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three human costimulatory molecules (B7.1, ICAM-1 and LFA-3, designated as TRICOM). Patients received booster vaccines with recombinant fowlpox containing the same four transgenes. 12/32 patients showed declines in serum PSA and 2/12 showed evaluable decrease in index lesions. Median OS was 26.6 months. Patients with greater PSA-specific T-cell responses showed a trend (p=0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs no GM-CSF. Patients with a Halabi predicted survival of 20% in the size of large liver metastasis. This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. Dr. Gulley and his colleagues in the Laboratory of Tumor Immunology and Biology (LTIB) and the Medical Oncology Branch (MOB), Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY12-13 the following collaborative vaccine clinical trials at the NCI Clinical Center. An open label pilot study to evaluate the safety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination with Sargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trial employed vectors with transgenes of both multiple tumor antigens and multiple costimulatory molecules. This includes a breast cancer patient who initially had a PR followed by a durable CR for over 5 years. This trial was recently published in Clinical Cancer Research. An open label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastatic CEA-expressing carcinoma. This is a first in humans trial for this vaccine and demonstrated safety of this approach. This trial recently completed accrual and a manuscript has been submitted. An open label pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-small cell lung cancer (NSCLC). Immunologic response to this agent is the primary endpoint. This trial has completed accrual. A manuscript on this study was recently publsihed. A phase I study to determine the safety and feasibility of an intraprostatic PSA-based vaccine in men with prostate cancer and local failure following radiotherapy or cryotherapy or clinical progression on androgen deprivation therapy in the absence of local definitive therapy. This study showed significant intratumoral infiltrates following vaccination. A manuscript on this study was recently published. A randomized, double-blind, phase 3 efficacy trial of PROSTVAC-V/F GM-CSF in men with asymptomatic or minimally symptomatic metastatic, castrate-resistant prostate cancer has recently opened based on the previously mentioned phase II. This study will recruit about 1,200 men with prostate cancer in approximately 22 countries. Dr. Gulley is the global PI for this study. A phase I dose escalation study of an antibody targeting double stranded DNA (NHS) conjugated to IL-12 is underway. A phase I dose escalation study of yeast-brachyury is underway. Brachyury expression is involved in drug resistance, EMT and other stem cell like properties. A phase I dose escalation study of an anti-PDL1 antibody in patients with solid tumors. Dr. Gulley is the coordinating PI of this first-in-human study of this agent sponsored by our CRADA partner, EMD-Serono. All the patients on the dose escalation portion will be enrolled at the NCI and others will be enrolled at other centers in expansion cohorts. Collaborative Trials with Extramural Cancer Centers A phase II study of PROSTVAC-V(Vaccinia)/TRICOM and PROSTVAC-F(fowlpox)/TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer. (Eastern Cooperative Oncology Group) Study completed, manuscript recently submitted. A phase I study of intravesical recombinant fowlpox-GM-CSF and or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ) Study completed. A phase I study of intratumoral recombinant fowlpox PANVAC (PANVAC-F) plus subcutaneous recombinant vaccinia PANVAC (PANVAC-V), PANVAC-F and recombinant granulocyte-macrophage colony stimulating factor (rH-GMCSF) in pancreatic cancer patients. (Cancer Institute of New Jersey, CINJ) Trial ongoing. A phase II study of active immunotherapy with PANVAC or autologous, cultured dendritic cells infected with PANVAC after complete resection of hepatic metastases of colorectal carcinoma. (Duke Comprehensive Cancer Center). This study was recently published.